It has been reported that chronic methamphetamine (MA) treatment decreases monoamine release in different brain regions. However, the clearance of norepinephrine (NE) after chronic MA intake is still not defined. In the present study, we administered MA to Sprague-Dawley rats for one month. The animals were later anesthetized with urethane for electrophysiological recording. Previous studies have indicated that GABA -induced electrophysiological responses are enhanced by NE acting via postsynaptc b-adrenergic receptors. We found that local application of the NE high affinity uptake blocker desmethylimipramine (DMI) significantly potentiated GABA -induced electrophysiological depressions in the cerebellar Purkinje neurons in control rats. In contrast, DMI did not augment GABA responses in rats chronically treated with MA for one month, or in rats withdrawn from MA for 7 to 14 days after one month of MA treatment. To further examine if DMI-induced GABA modulation is altered by post- or pre-synaptic mechanisms in chronic MA treated rats, we examined the electrophysiological interaction of GABA and isoproterenal (ISO), a postsynaptic b- adrenergic receptor agonist, in Purkinje neurons. We found that GABA - induced inhibition is potentiated by local application of ISO in both control and chronic MA rats, suggesting that the reduction in DMI/GABA action is probably not mediated through post-synaptic noradrenergic mechanisms. Presynaptic NE clearance was further examined using in vivo chronoamperometric methods. Extracellular NE levels in the cerebellar cortex were measured using Nafion-coated carbon fiber sensors. We found that local application of DMI inhibited NE clearance in control, but not in chronic MA, rats suggesting that presynaptic NE clearance is reduced after chronic MA treatment. In conclusion, our data suggest that regulation of uptake by DMI at central noradrenergic nerve terminals is abnormal after chronic MA exposure, which results in attenuation of DMI-induced GABA modulation. - Methamphetamine, Neurodegeneration, Neuroprotection, Dopamine, Ischemia